Life Extension Magazine December 2013
A Natural Arsenal for Prostate Cancer Prevention
By Michael Downey
Use of pomegranate (Punica granatum L. var. spinosa ) juice, peel, and oil has been shown to possess anticancer activities, including interference with tumor cell proliferation, cell cycle, invasiveness, and angiogenesis.129 Apoptosis was implicated as a mechanism for this interference with prostate cancer cell proliferation in a laboratory study in which researchers found that pomegranate extract increases expression of a protein that promotes cancer cell death, while decreasing expression of a protein that inhibits cancer cell death.130 Later, in a 2012 study, scientists found that the in vitro cytotoxic activity of an extract of pomegranate against prostate cancer cells was dose-dependent—and they also suggested that this antiproliferative effect followed an apoptosis-dependent pathway.131
Further clarifying pomegranate’s effects against prostate cancer cells, scientists found evidence of induced beneficial gene expression—inhibiting pro-inflammatory, DNA-related protein nuclear factor kappa B (NF-kB)132 and downregulating production of cancer-stimulating androgen receptors in prostate cells.133 The suggested dosage for prostate cancer prevention is 80-120 milligrams daily (of punicalagins), and for adjuvant cancer therapy, 280-375 milligrams daily (of punicalagins), with or without food.
18. Saw Palmetto
Saw palmetto (Serenoa repens or Sabal serrulata) is now one of the most widely used phytotherapies for BPH (benign prostatic hyperplasia) in the US,134,135 a condition characterized by an enlarged prostate gland. However, evidence has been emerging that saw palmetto also has biological activity in prostate cancer cells and may defend against prostate cancer.136 For instance, a saw palmetto extract was shown to inhibit the activity of 5-alpha-reductase,137 an enzyme that converts testosterone to the most potent androgen and that is involved in the pathway of prostate cancer. Saw palmetto also appears to have anti-inflammatory properties and—crucially—a tendency to promote apoptosis in prostate cancer cells.138,139
In one study, researchers described how they used saw palmetto extract to slow the growth of prostate cancer cells in vitro. This growth-inhibitory effect was more potent on prostate cancer cells than on other cancer cell lines on which they tested saw palmetto.140 One new mechanism identified by this group of scientists was the saw palmetto-induced reduction in the expression of cyclooxygenase-2 (COX-2) in prostate cancer cells. Cancer cells often use COX-2 as biological fuel to hyperproliferate, and as the researchers presenting this report concluded, “We hypothesize that COX-2 inhibition induced by saw palmetto berry extract may provide an important basis for potential chemopreventative action.” 140 A typical suggested dose of saw palmetto is 320 milligrams daily.
By working through over a dozen anticancer mechanisms and selectively targeting cancer cells, resveratrol inhibits prostate cancer at multiple stages of development.141 This potent compound, found in grapes and other plants, was first isolated in 1940 and is now viewed as a potential defense against this disease.141-143 In a study that examined the effect of various polyphenols on different types of prostate cancer cells, scientists concluded that resveratrol was the most potent against advanced prostate cancer cells.144
Resveratrol has the ability to modulate the activity of estrogen and testosterone at both the cellular (receptor) and molecular (genetic) levels.145-147 In fact, after examining its effects on hormone-responsive genes in prostate cancer cells, researchers concluded that, “Resveratrol may be a useful chemopreventive/chemotherapeutic agent for prostate cancer.”147 Also, resveratrol reverses increases in PSA in cancer cells.147,148 For example, in one study, four days of resveratrol treatment resulted in an 80% reduction in PSA levels in prostate cancer cells.148 Resveratrol also modulates growth factors, protects DNA, blocks cancer-causing chemicals and radiation, and fights free radicals and inflammation.149,150 The same anticancer gene activated by non-steroidal anti-inflammatory drugs (NSAIDs) demonstrates enhanced expression by resveratrol.151
Using a DNA microarray—a scientific research tool that simultaneously examines how particular phytocompounds affect thousands of genes—scientists found that resveratrol exerts a striking effect on cancer-related genes. Among other things, resveratrol activates tumor suppressor genes, other genes that destroy cancer cells, and genes that control the cell cycle—while suppressing genes that allow cancer cells to communicate with one another.152 This ability to get inside cancer cells and activate or deactivate genes is a powerful weapon against cancer growth—especially since resveratrol exerts its effects without toxicity.145 Many resveratrol supplements on the market are diluted. For pure resveratrol, the suggested dosage is 20-250 milligrams a day, taken with or without food.
20. Supplemental Lignans
Many different plant sources provide rich sources of lignans—and this may partially explain why men who eat healthier diets enjoy sharply reduced rates of prostate cancer.153,154 Lignan molecules are involved in plant defense mechanisms.154 But experimental evidence suggests that dietary lignans also offer humans significant protection against tumors in a variety of organs—including tumors of the prostate.155-158 In fact, researchers found that men with higher blood levels of lignans have the lowest incidence of prostate cancer.10 Bacteria in the intestines convert dietary and supplemental lignans into mammalian lignan compounds called enterolactones, which enter the bloodstream.159
Findings from human, animal, and in vitro studies indicate that enterolactones protect against hormone-dependent cancers.160-162 Tyrosine kinases are activated in metastatic prostate cancer cells, and enterolactones help to inhibit the tyrosine kinase enzyme.163 Enterolactones have been shown to inhibit 5-alpha-reductase, an enzyme that converts testosterone to a more potent androgen.164 Anti-angiogenesis effects and cancer-cell apoptosis were found to be enhanced by enterolactones in animal models of hormone-related cancers, including prostate cancer.165,166 Enterolactone also functions via several mechanisms to reduce estrogen input to cells and has been shown in a number of studies to be a factor in the development of benign prostate enlargement and prostate cancer.162,167-170
A dosage of 20-50 milligrams daily of lignans is suggested to defend against prostate cancer. For adjuvant prostate cancer support, 75-125 milligrams daily is suggested.
21. Vitamin K
The anti-tumor potential of vitamin K has been a part of scientific research since 1947.171 Researchers have observed tumor cell destruction in prostate cancer patients following supplementation with a combination of vitamin C and vitamin K3, the synthetic form of vitamin K.172 (This same combination was later developed into the prostate cancer drug Apatone®, which has shown similar results.173)
Subsequently, a study that followed 11,319 men for an average of 8.6 years found that those with the highest intake of vitamin K2 were 63% less likely to develop advanced prostate cancer.174 The same research team found no effect on prostate cancer from vitamin K1 supplementation. Optimum prostate cancer prevention dosages for vitamin K2 are not known, but typically suggested daily dosages are 1,000 micrograms for the menaquinone-4 form of K2 (MK-4) and 200 micrograms for the menaquinone-7 (MK-7) form.
A plant fat and phytosterol known as beta-sito-sterol, used in several European prostate drugs, has been found to block the growth of prostate cancer cells. A study on an androgen-dependent line of prostate cancer cells showed that beta-sitosterol decreased cancer cell growth by 24% and increased apoptosis four-fold.175 These findings correlated with a 50% increase in production of ceramide,175 an important cell membrane component believed to induce apopotosis.176
In another study, an androgen-dependent line of human prostate cancer cells (PC-3 cell line) was implanted in mice, and scientists compared both the in vivo and in vitro effects of a 2% mixture of beta-sitosterol with those of a 2% mixture of cholesterol on these cells. Compared to controls, beta-sitosterol, as well as another phytosterol known as campesterol, inhibited growth of the prostate cancer cells by 70% and 14%, respectively.177 By contrast, the cholesterol mixture increased cell growth by 18%. Various other parameters were also measured.
For example, the phytosterol mixtures inhibited the invasion of the prostate cancer cells into Matrigel-coated membranes—a measure of cancer invasiveness—by 78%, compared to controls, while the cholesterol mixture increased invasiveness by 43%.177 Also, migration of the prostate tumor cells through 8-micron pore membranes—a measure of tumor motility—was reduced by 60-93% when they were in the phytosterol mixtures, but it was increased by 67% when in the cholesterol.177 In a measure of adhesiveness and ability to form tumor clumps, phytosterol supplementation reduced the binding of these cancer cells to laminin by 15-38% and to fibronectin by 23%, while cholesterol increased cell-binding to type IV collagen by 36%.177 The research team concluded that—indirectly in vivo as a dietary supplement, and directly in vitro in tissue culture media—phytosterols inhibited the growth and metastasis of these (PC-3) prostate cancer cells. Beta-sitosterol, however, was determined to be much more effective than campesterol in offering this protection in most parameters assessed.177
In later research on the mechanism involved, scientists determined that phytosterols such as beta-sito-sterol may induce the inhibition of tumor growth by stimulating apoptosis and arresting cells at different locations in the cell cycle, and that this may involve alterations in reactive oxygen species and production of prostaglandin.178 A suggested phytosterol dosage is 169 milligrams twice daily with or without food.
In studies on human cancer cells, scientists observed that the vegetable extract apigenin inhibits angiogenesisand cell proliferation.179-181 These effects were confirmed in an animal experiment in which scientists transplanted an androgen-dependent line of human prostate cancer cells into mice bred to serve as a model for tumor growth conditions.182 A liquid suspension containing either apigenin or placebo was given to the mice daily, via a gastric tube, for eight or ten weeks. Administering apigenin to mice—beginning either two weeks before, or two weeks after, inoculation with the cells—inhibited the volume of prostate cancer cells in a dose-dependent manner by as much as 59% and 53%, respectively.182 Induction of apoptosis in the tumor xenografts was observed. In the same study, exposure of prostate cancer cells to apigenin in a culture for as little as 24 hours appeared to inhibit cell cycle progression by nearly 69%.182
Scientists believe these effects may result from apigenin’s modulation of the IGF (insulin-like growth factors) axis, which plays signaling roles in cell proliferation and cell death.183 Later research demonstrated that apigenin also inhibits motility and invasiveness of prostate carcinoma cells.184 The importance of supplementation for prostate protection is reflected in the fact that Americans typically consume only 13 milligrams of flavonoids (including flavones like apigenin) daily,183 however a suggested apigenin preventive dosage is 25-50 milligrams daily, and adjuvant dosage for prostate cancer patients may exceed 100 milligrams daily.
24. Ginger (Zingiber officinale)
A study reported in 2013 demonstrated that ginger phytochemicals work synergistically to inhibit the proliferation of human prostate cancer cells (PC-3 cell line).185 In past research, ginger showed anti-inflammatory, antioxidant, and antiproliferative activities, suggesting a promising role as a chemopreventive agent.186,187 Then, a 2012 study became the first report to clearly demonstrate the anticancer activity of orally taken, whole ginger extract for the therapeutic management of prostate cancer.187 This breakthrough research found that ginger resulted in growth inhibition, cell-cycle arrest, and induced caspase-dependent intrinsic apoptosis in prostate cancer cells.187 In vivo studies by this team showed that—without any detectable toxicity—ginger significantly inhibited tumor growth in xenografts of a line of prostate cancer cells (PC3) subcutaneously implanted in nude mice.187
Specifically, the scientific team orally fed a solution containing ginger extract to the tumor-implanted mice for eight weeks. Daily measurements of tumor volume were performed. Tumors in control mice that received a placebo solution showed unrestricted growth. But tumors in mice that received the ginger extract solution showed a time-dependent inhibition of growth over the eight-week period. Remarkably, the tumor burden in the ginger group was reduced by about 56% after just eight weeks of feeding.187 Tumor tissue from ginger extract-treated mice showed a reduced proliferation index and “widespread apoptosis” compared with controls.187 Ginger treatment was well tolerated, and the test mice maintained normal weight gain and showed no signs of discomfort during the treatment regimen. Most importantly, orally taken ginger extract did not exert any detectable toxicity in normal, rapidly dividing tissues such as the gut and bone marrow.
Although further research is urgently needed, this study suggests that ginger extract has anticancer effects against human prostate cancer cells. No dosage for this purpose has been determined, but the study team performed allometric scaling calculations to extrapolate the mice dosage to humans. The human equivalent dose of ginger extract was found to be approximately 567 milligrams daily for a 154-pound (70 kilogram) human adult.187,188 This may be viewed as an adjuvant therapy dosage, and an appropriate preventive dosage would be significantly less.
25. Inositol Hexaphosphate (IP6)
Inositol hexaphosphate, or IP6, is a phytochemical found in cereals, soy, legumes, and other fiber-rich foods.189 Building on earlier in vitro research showing that IP6 strongly inhibits growth and induces differentiation of human prostate cancer cells (PC-3 cells),190 scientists designed an animal study. They injected mice with a line of human prostate cancer cells (DU145 cells) and then gave them either normal drinking water or water that included 1% or 2% IP6 for 12 weeks. The hormone-refractory (castration-resistant) prostate cancer growth was reduced 47% in the 1% IP6-solution mice and reduced 66% in the 2% IP6-solution mice, compared to littermates without the IP6-enriched drinking water diet.191
Then, in 2013, scientists designed an IP6 experiment on TRAMP mice, which are genetically modified to develop metastatic prostate cancer.192 For 24 weeks, mice with prostate cancer were given drinking water that was 0%, 1%, 2%, or 4% IP6. The study team periodically conducted magnetic resonance imaging (MRI) tests on each mouse prostate to assess prostate volume and tumor vascularity. The animals that received higher concentrations of IP6 showed a “profound” reduction in prostate tumor size, due in part to the compound’s antiangiogenic effect (the ability of the compound to reduce new blood vessel formation).192 The researchers discovered a decrease in a glucose transporter protein, known as GLUT-4, in the prostates of IP6-treated mice, and observed that IP6 decreased glucose metabolism and membrane phospholipid synthesis—meaning there was substantial energy deprivation with the tumor itself. This demonstrates “a practical and translational potential of IP6 treatment in suppressing growth and progression of prostate cancer in humans.”192